Recent work from the sponsor's laboratory demonstrated that mutations in the ACTN4 gene, encoding (alpha-actinin- 4, cause a form of inherited disease known as focal segmental glomerulosclerosis. In this project, I will utilize a recently developed "knockout" mouse model to study the role of (alpha-actinin-4 in cell function, with an emphasis on podocyte biology. Mice deficient in ACTN4 demonstrate proteinuria, altered podocyte morphology, and progressive kidney failure. We will use fibroblasts and glomerular podocytes derived from ACTN4 deficient and wild-type mice to study the role of this protein in cell adhesion, cell motility, and cytoskeletal function. In order to better understand the downstream biologic effects of ACTN4 and ACTN4-deficiency, we will use Microarray technology to compare gene expression patterns in wild-type and mutant cells. These studies should help elucidate the function of ACTN4, and yield new insights into the pathogenesis of kidney disease.